BF: So, is that really adoption and buying into it and being believers? Or is it more of a heavy hand?
FT: I believe it’s a very confused picture, right? Because what we see is the end result of many confounding factors in which you have different incentives or disincentives in the system. We see a number of different policy interventions in many different countries, where policymakers are trying to learn about what the promise of biosimilars for the healthcare systems could be. They are kind of trying different instruments, trying to understand what are best practices, and which can be adopted in different parts of the world.
BF: All right, so Frank, I am a reference brand manufacturer, and I’m listening to the Florians of the world speak, and I’m concerned about their irrational exuberance over the unproven, and I want to do the trials, with real-world evidence, that are going to show them that the brand drug which I’ve invested in and spent the past 20 years promoting is the better product. What’s that trial look like?
FE: That’s a great question. I’m not sure I have the answer.
BF: There are a lot of people in the room who would really like to know.
FE: Yes, well thank you for that.
SN: Just one point—it can’t be better. It just can’t be better, because by definition, it’s biosimilar. So it can’t be better. It has to have similar efficacy, similar safety.
BF: If you go by resource utilization, it could be non-inferior. But if you use cost as a metric, it could be better.
SN: Ok, so, from a cost perspective, yes.
BF: Right, but the concern would be what do we know about, if we’re going to go with more traditional efficacy and toxicity, and we’re going to look at those aspects, because that’s not what’s available in a clinical trial. And to some degree, is the real-world population different from the trial population? And is that a difference that you could show? That could be meaningful, because it’s going to be a population which is less enriched and potentially sicker. So I don’t know. Where would you go with that if that’s your charge? Design that study for us.
FE: So it’s not going to be a clinical trial, but it could be a pragmatic trial. It could be database research once the data start to come in, relying of course on the utilization to be there in order to be able to analyze it. I think with the databases that are available in different places around the world, you’re going to have very deep and ripe areas of research to answer lots of different questions: regulatory uncertainty, complexity of production, interchangeability or substitutability, competition, and a new term: “biobetters.”
BF: Florian invented it.
FT: I mean, I don’t know what the perfect study design is, right? One key hypothesis which was subject to a study was NOR-SWITCH, and it was about switching. I think it was quite an important study.
SN: I think the beauty of real-world evidence for biosimilars is the fact that the regulatory pathway only requires you to do a clinical trial in the most sensitive population, and RWE provides a mechanism for those indications that haven’t been studied in the clinical trial environment.
BF: I would think the reference brands might want to know, before the introduction of a biosimilar, what does the current real world look like for their brand across the disease in which it is indicated? That could be very, very different from a clinical trial in terms of the comorbidities of these patients, the age of these patients, the complexity of disease of the patients, the actual diseases themselves, what are the resource utilizations costs, the patterns of care. Is it being used in the first line, second line, third line, and in what sequence? You would think the brands would want to know the landscape so that when the biosimilar comes into the marketplace, you can really measure and study it. It seems like it’s almost happening after the fact: “Oh my God, the biosimilar’s in the market; we’d better look at this now.” And I’m surprised that there hasn’t been more of that. Was there those types of studies being done in Europe by the reference brands in order to really get a handle on their current position?
GF: Certainly, with the growth hormones. I mean, a lot of the manufacturers were having big databases, registries, so that physicians could go in there and they could enter all the patient data, and they could monitor it, and they could track it themselves, and the physicians really liked these registries, because they could really see how the product was impacting patients. And they have massive amounts of data there. You can demonstrate the true efficacy in more than one of the populations. And that’s where I see real-world data going with regard to biosimilars.
BF: I’m curious where you think we’re going to be in 5 more years with biosimilars. And particularly in regard to separately, what will be happening in Europe, and what will be happening in the US?
GF: So personally, I think it comes down to trust, and trust building. And I think that’s what’s going to have to happen over the next 5 years with all of the stakeholders. We are seeing it at sort of the national payer level in Europe at the moment. I think there’s an element of trust in biosimilars: The regulatory bodies have approved them. They’re having processes in place that you can get access. I think where we’re seeing the challenges now is more at the local level. I’ve come across a number of cases where the biosimilar manufacturers just can’t get access at the local level because the local systems aren’t set up to accommodate for a biosimilar and a branded product on their formulary. I think those issues will be ironed out over the next 5 years, and I think we will see an increase in uptake of biosimilars as the cost benefits are seen, but also as all of the stakeholders begin to understand that they are similar. These products are similar and can result in cost savings because the clinical effects that they are seeing are comparable.
FT: So, in 5 years from now, we will have all internalized the concept of biosimilars and of extrapolation, and we will start to get excited about it.
And 5 years from now, I would expect, at least in a critical mass of markets, we will not have those artificial price discussions. Is it a 20% discount? Is it more? I think we will start to learn in the calibration process what is likely the right balance between procurement instruments, price, number of provider suppliers you need in the market, and what is needed for, on the one side, a sustainable business, and on the other side, sustainability of care, particularly when it comes to oncology.
Which brings me to the third point: In 5 years from now, we will hopefully have very reinforcing experience as well in life-threatening diseases, and people won’t make this artificial distinction anymore between supportive care, life-threatening diseases, or others.
SN: So, I think we’ll see a difference between Europe and the US, to start. I think in Europe, you will definitely see increased uptake of biosimilars outside of the Nordics, but also in the other European countries. So we’re starting to see uptake of around 30%. I think that will increase. And you’ll have more biosimilars coming to the market. I mean, we have a second infliximab biosimilar entering the market in Europe. I think you’ll see different policies coming in Europe that Florian was mentioning earlier, about the quota systems in Germany. We’re seeing quotas where you have to use biosimilars, but they’re pretty low—you know, 6%, 7%, 8%. But you’ve also got fixed reference price groups, which you see in Spain. So as soon as a biosimilar enters the market, you’ve got a fixed reference price group, which means the reference product and the biosimilar come down to the same price.
I think the difference in the US will be seeing how many biosimilars get approved. So we’ve seen an adalimumab/Humira biosimilar get FDA approval. We’ve got an etanercept/Enbrel biosimilar approval in the US. But the launch possibilities are a long way off because of patent issues. So even in 5 years, we still may not see an etanercept biosimilar, but hopefully we will see a Humira biosimilar. But you know, the originator has come out and said they don’t expect to see biosimilars in the market in the US until 2022. There’s still a lot of barriers in the US. You don’t have—the FDA has not even issued their guidance on interchangeability. [Since this talk, FDA issued draft guidance regarding considerations in demonstrating interchangeability with a reference product in January 2017.]
FE: I think some of the—I’ll say it in a somewhat different way— I think some of the misperceptions or that doubts related to interchangeability or the utility of different agents will not be at the forefront of the questions being answered or asked. I think in terms of research questions, they will be different.
BF: I’m sorry guys, but we’ve run out of time. What a wonderful problem to have. I want to thank all of you in the audience for coming out this early in the morning, some without a first cup of coffee. I want to thank my panelists, Graham, Florian, Sue, and Frank.
And I’ll leave you with a final thought: In 5 years, will innovations like immuno-oncology obviate all the benefits of biosimilars because we will have eclipsed the class of reference drugs upon which they are built and moved on to something new?